Although there are published studies of proline biochemistry and nutrition in cultured cells and postnatal animals, little is known about proline metabolism and function in the conceptus (embryo/fetus, associated placental membranes, and fetal fluids). Because of the invasive nature of biochemical research on placental and fetal growth, animal models are often used to test hypotheses of biological importance. Recent evidence from studies with pigs and sheep shows that proline is a major substrate for polyamine synthesis via proline oxidase, ornithine aminotransferase, and ornithine decarboxylase in placentae. Both porcine and ovine placentae have a high capacity for proline catabolism and polyamine production. In addition, allantoic and amniotic fluids contain enzymes to convert proline into ornithine, which is delivered through the circulation to placental tissues. There is exquisite metabolic coordination among integrated pathways that support highest rates of polyamine synthesis and concentrations in placentae during early gestation when placental growth is most rapid. Interestingly, reduced placental and fetal growth are associated with reductions in placental proline transport, proline oxidase activity, and concentrations of polyamines in gestating dams with either naturally occurring or malnutrition-induced growth retardation. Conversely, increasing proline availability in maternal plasma through nutritional or pharmacological modulation in pigs and sheep enhances concentrations of proline and polyamines in placentae and fetal fluids, as well as fetal growth. These novel findings suggest an important role for proline in conceptus metabolism, growth and development, as well as a potential treatment for intrauterine growth restriction, which is a significant problem in both human medicine and animal agriculture.
This study was designed to determine whether pyrroline-5-carboxylate (P-5-C) synthase is deficient in chick enterocytes therefore resulting in the lack of synthesis of ornithine and citrulline from glutamine. Post-weaning pig enterocytes, which are known to contain P-5-C synthase and to synthesize both ornithine and citrulline from glutamine, were used as positive controls. Enterocytes were incubated at 37 degrees C for 0-30 min in the presence of 2 mM [U-14C]glutamine or 2 mM ornithine plus 2 mM NH4Cl. In chick enterocytes, glutamine was metabolized to NH3, CO2, glutamate, alanine and aspartate, but not to ornithine, citrulline, arginine or proline. Likewise, there was no formation of citrulline, arginine, alanine or aspartate from ornithine in chick enterocytes. Furthermore, the rate of conversion of ornithine into proline in chick enterocytes was only about 4% of that in cells from pigs. To elucidate the reason for the inability of chick enterocytes to synthesize ornithine and citrulline from glutamine, the activities of the enzymes involved were measured. No activity of P-5-C synthase or ornithine carbamoyltransferase was found in chick enterocytes, in contrast with cells from post-weaning pigs. It was also demonstrated that the activity of ornithine aminotransferase in chick enterocytes was only 3% of that in cells from pigs. Thus the present findings elucidate the biochemical reason for the lack of endogenous synthesis of ornithine and citrulline in chicks. Our results also explain previous observations that ornithine cannot replace arginine or proline in the diet of chicks. We suggest that the absence of P-5-C synthase and ornithine carbamoyltransferase in enterocytes is the metabolic basis for the nutritional requirement of arginine in the chick.
Polyamines are essential for embryonic and fetal survival, growth, and development. Additionally, polyamines may induce autophagy in mammalian cells. However, little is known about the availability of polyamines or autophagy in the porcine conceptus with intrauterine growth restriction (IUGR). The present study was performed to evaluate the developmental changes of polyamine concentrations in IUGR and normal porcine fetuses as well as autophagic marker levels in the fetal intestinal mucosa during the second half of gestation when most fetal growth occurs. Allantoic fluid (ALF), amniotic fluid (AMF), umbilical vein, and the small-intestinal mucosa were obtained from both IUGR and normal fetal pigs at d 60, 90, and 110 of gestation. Concentrations of polyamines in fetal fluids as well as protein abundances of microtubule-associated protein light chain 3B (LC3B), an autophagic marker, in the fetal small-intestinal mucosa were determined. Concentrations of polyamines varied greatly in different fetal compartments and changed substantially with advancing gestation. Concentrations of polyamines in IUGR fetal fluids and the small-intestinal mucosa were markedly different from those in their normal counterparts at d 60 and 90 of gestation, whereas most of the differences were not detected by late (d 110) gestation. Specifically, polyamine levels were lower in the umbilical vein plasma but higher in ALF and AMF from IUGR fetuses. Furthermore, enhanced levels of an autophagic marker were observed in the small-intestinal mucosa of IUGR fetuses throughout mid and late gestation in association with abnormal spermidine levels in fetal plasma. These findings support the notion that enhanced autophagy may be an important survival mechanism in IUGR fetuses. Collectively, our findings provide a new framework for future studies to define the roles for polyamines in the prevention and treatment of IUGR in both human medicine and animal production.
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